Clinical Trial of the ATM-Inhibitor WSD0628 in Combination With Radiation Therapy for Recurrent Brain Tumors

Inclusion Criteria:

• Age ≥ 18 years

• Histological confirmation of one of the following:

• Glioblastoma, IDH-wildtype

• Grade 3 or 4 IDH1/2 mutant astrocytoma (2021 WHO classification)

• Measurable disease as defined in Section 11.0

• Disease progression after previous treatment for glioma with radiation andchemotherapy

• Minimum life expectancy of at least 3 months

• Group C only: Dose Expansion, Brain Tumor Penetration Group: plan for radiosurgeryand surgical resection as part of routine clinical care

• ECOG Performance Status (PS) 0, 1 or 2 (Appendix I)

• The following laboratory values obtained ≤15 days prior to registration:

• Hemoglobin ≥9.0 g/dL

• Leukocytes ≥3.0 x 109/L

• Absolute neutrophil count (ANC) ≥1500/mm3 or 1.5 x 109/L

• Platelet count ≥100,000/mm3 or 100 x 109/L

• Total bilirubin ≤1.5 x ULN and <3 mg/dL for patients with Gilbert's disease

• Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤3 x ULN

• PT/INR/aPTT ≤1.5 x ULN OR if patient is receiving anticoagulant therapy and INRor aPTT is within target range of therapy

• Calculated creatinine clearance ≥45 ml/min using the Cockcroft-Gault formula below:

• Creatinine clearance for males = (140-age)(weight in kg)(72)(serum creatinineinmgdL⁄)

• Creatinine clearance for females = (140-age)(weight in kg)(0.85)(72)(serumcreatinine inmgdL⁄)

• Negative pregnancy test done ≤7 days prior to registration, for persons ofchildbearing potential only

• Willing to take light-protective measures during the study and for two weeks aftertheir last dose of WSD0628

• Provide written informed consent

• Willing to return to enrolling institution for follow-up (during the ActiveMonitoring Phase of the study)

• Willingness to provide mandatory tissue specimens for correlative research

Exclusion Criteria:

• Any of the following because this study involves an investigational agent, thegenotoxic, mutagenic, and teratogenic effects of which on the developing fetus andnewborn are unknown:

• Pregnant persons

• Nursing persons

• Persons of childbearing potential and persons able to father a child who areunwilling to employ adequate contraception

• Uncontrolled intercurrent illness including, but not limited to:

• ongoing or active infection

• symptomatic congestive heart failure

• unstable angina pectoris

• cardiac arrhythmia

• or psychiatric illness/social situations that would limit compliance with studyrequirements

• Any of the following cardiac criteria:

• Marked baseline prolongation of QT/QTc interval (e.g., repeated demonstrationof a QTc interval >480 milliseconds (ms) (CTCAE Grade 1) using Fredericia's QTcorrection formula.

• History of additional risk factors for Torsades de Pointes (e.g., heartfailure, hypokalemia, family history of Long QT. Syndrome).

• Use of concomitant medications that prolong the QT/QTc interval

• History of myocardial infarction ≤6 months prior to registration, or congestiveheart failure requiring use of ongoing maintenance therapy for life-threateningventricular arrhythmias

• Known coagulopathy increasing the risk of bleeding or history of clinicallysignificant hemorrhage, including significant intracranial tumor related hemorrhage

• Any of the following medications:

• Enzyme-inducing anticonvulsants within two weeks of enrollment NOTE: Patientscan be enrolled after a change to non-enzyme inducing anticonvulsants)

• Patients taking more than 8 mg of dexamethasone per day (or equivalent steroiddose) at time of enrollment

• Any of the following prior therapies:

• Radiation therapy <= 26 weeks prior to registration (including gamma tiles)

• Chemotherapy, immunotherapy, bevacizumab or any investigational drug <= fourweeks prior to registration,

• or carmustine (BCNU) or lomustine (CCNU) <= six weeks prior to registration

• Past medical history of interstitial lung disease, drug-induced interstitial lungdisease, radiation pneumonitis which required steroid treatment, or any evidence ofclinically active interstitial lung disease

• History of hypersensitivity to active or inactive excipients of WSD0628 or drugswith a similar chemical structure or class to WSD0628

• Refractory nausea and vomiting if not controlled by supportive therapy, chronicgastrointestinal diseases, inability to swallow the formulated product or previoussignificant bowel resection that would preclude adequate absorption of WSD0628

• Uncontrolled hypertension

• History of severe brain-injury or stroke

• Receiving any other investigational agent which would be considered as a treatmentfor the primary neoplasm